1. Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate.
- Author
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Bibby JA, Purvis HA, Hayday T, Chandra A, Okkenhaug K, Rosenzweig S, Aksentijevich I, Wood M, Lachmann HJ, Kemper C, Cope AP, and Perucha E
- Subjects
- Animals, Antigens, CD19 metabolism, Class I Phosphatidylinositol 3-Kinases metabolism, Coculture Techniques, Hereditary Autoinflammatory Diseases metabolism, Humans, Macrophages metabolism, Metabolic Syndrome metabolism, Mevalonate Kinase Deficiency metabolism, Mice, Phosphatidylinositol 3-Kinases metabolism, Positive Regulatory Domain I-Binding Factor 1 metabolism, Principal Component Analysis, Signal Transduction, Th1 Cells metabolism, Toll-Like Receptor 9 metabolism, Tumor Necrosis Factor-alpha metabolism, B-Lymphocytes, Regulatory metabolism, Cholesterol metabolism, Interleukin-10 metabolism, Polyisoprenyl Phosphates metabolism
- Abstract
Regulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) is required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications control signaling through PI3Kδ-AKT-GSK3, which in turn promote BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cells from MKD patients induce poor IL-10 responses and are functionally impaired. Moreover, metabolic supplementation with GGPP is able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells.
- Published
- 2020
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